Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity
Seungjin Ryu, Olga Spadaro, Sviatoslav Sidorov, Aileen H. Lee, Sonia Caprio, Christopher Morrison, Steven R. Smith, Eric Ravussin, Irina Shchukina, Maxim N. Artyomov, Yun-Hee Youm, Vishwa Deep Dixit
Seungjin Ryu, Olga Spadaro, Sviatoslav Sidorov, Aileen H. Lee, Sonia Caprio, Christopher Morrison, Steven R. Smith, Eric Ravussin, Irina Shchukina, Maxim N. Artyomov, Yun-Hee Youm, Vishwa Deep Dixit
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Research Article Inflammation Metabolism

Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity

Abstract

The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet–induced (HFD-induced) obesity increased SPARC expression in adipose tissue. Inducible SPARC downregulation in adult mice mimicked CR’s effects on lowering adiposity by regulating energy expenditure. Deletion of SPARC in adipocytes was sufficient to protect mice against HFD-induced adiposity, chronic inflammation, and metabolic dysfunction. Mechanistically, SPARC activates the NLRP3 inflammasome at the priming step and downregulation of SPARC lowers macrophage inflammation in adipose tissue, while excess SPARC activated macrophages via JNK signaling. Collectively, reduction of adipocyte-derived SPARC confers CR-like metabolic and antiinflammatory benefits in obesity by serving as an immunometabolic checkpoint of inflammation.

Authors

Seungjin Ryu, Olga Spadaro, Sviatoslav Sidorov, Aileen H. Lee, Sonia Caprio, Christopher Morrison, Steven R. Smith, Eric Ravussin, Irina Shchukina, Maxim N. Artyomov, Yun-Hee Youm, Vishwa Deep Dixit

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Figure 7

Adipocyte-derived SPARC controls macrophage inflammation.

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Adipocyte-derived SPARC controls macrophage inflammation. (A and B) Sche...
(A and B) Schematic and weight change of Con and Adip-KO mice with 21 weeks of HFD followed by 13 weeks of chow diet (n = 5, 5, respectively). (C) Body composition analysis of female Con and Adip-KO mice before and after diet change from HFD to chow diet (n = 4, 4, respectively). (D and E) q-PCR analysis of inflammatory gene (D) and components of inflammasome (E) in VAT macrophages (F4/80+) in obese mice switched to chow diet (n = 4, 4, respectively). (F) Inflammasome activation after pretreatment of SPARC protein for 24 hours following ATP (5mM) treatment with or without LPS (1 μg/mL) measured by caspase-1 Western blot analysis in cell lysate (lower) and supernatant (upper). Error bars represent the mean ± SEM. 2-tailed unpaired t tests were performed for statistical analysis. *P < 0.05; **P < 0.01; ***P < 0.001.